The invention relates to a process for the preparation of 2-chloro-5-chloromethyl-1,3-thiazole (CCT).
2-Chloro-5-chloromethyl-1,3-thiazole is a valuable intermediate in the preparation of pesticides or pharmaceutical products.
A large number of extremely varied processes for the preparation of CCT are already known from the literature.
For example, EP 0 260 560 and EP 0 446 913 describe the preparation of CCT by reaction of allyl isothiocyanate and of allyl isothiocyanate substituted by a leaving group, respectively, with a chlorinating agent, and EP 0 763 531 describes the reaction of 2-chloroallyl isothiocyanate with a chlorinating agent. Those processes have disadvantages, because, for example in the case of the first variant, a plurality of secondary products are formed so that the CCT prepared has a low degree of purity, and in the case of the second variant the starting material is obtainable only at high cost. Furthermore, a considerable excess of chlorinating agent must be used and the operation must be carried out at a high dilution. In addition, it is necessary to adhere exactly to the reaction temperature and the stable intermediate formed in the course of the reaction has to be converted into the desired end product exothermically in an additional reaction step. As an improvement EP 0 794 180 describes the preparation of CCT from 1,3-dichloropropene and a thiocyanate salt via 3-chloro-1-isothiocyanato-1-propene.
Other variants, for example the process according to EP 0 775 700, according to which CCT is prepared via 2-amino-5-methylthiazole by means of diazotisation and subsequent chlorination, likewise exhibit the disadvantage that CCT is contaminated by a large number of secondary products which can scarcely be removed or can be removed only with great difficulty and with high losses of yield.
The aim of the invention was to provide a new process that enables CCT to be prepared in high purity and high yield.
The invention accordingly relates to a process for the preparation of 2-chloro-5-chloromethyl-1,3-thiazole, wherein allyl isothiocyanate of formula CH2xe2x95x90CHxe2x80x94CH2xe2x80x94NCS
a) is reacted at from xe2x88x9240xc2x0 C. to +30xc2x0 C., in a solvent that is inert under the reaction conditions, with from 1 to 2 mol of a chlorinating agent per mol of allyl isothiocyanate and
b) to the reaction mixture so obtained there is added, at a reaction temperature of from 0xc2x0 C. to the boiling temperature of the solvent used, from 1 to 5 mol of oxidising agent per mol of allyl isothiocyanate and
c) 2-chloro-5-chloromethyl-1,3-thiazole is isolated from the reaction mixture and
d) is optionally converted by crystallisation into high-purity 2-chloro-5-chloromethyl-1,3-thiazole.
The starting compound used according to the invention for the preparation of CCT is allyl isothiocyanate of formula CH2xe2x95x90CHxe2x80x94CH2xe2x80x94NCS.
That compound is reacted in step a) with a chlorinating agent.
Chlorinating agents that come into consideration are chlorine and compounds from which chlorine is liberated under the reaction conditions. Examples of such compounds are sulfuryl chloride, PCl5, PCl3, POCl3 etc.
The chlorinating agent is used according to the invention in an amount of from 1 to 2 mol per mol of allyl isothiocyanate. Preference is given to the use of from 1 to 1.6 mol and especially from 1 to 1.3 mol of chlorinating agent per mol of allyl isothiocyanate.
The reaction is carried out in a solvent that is inert under the reaction conditions. Suitable solvents are, for example, aliphatic or aromatic hydrocarbons, for example benzene, toluene, hexane, heptane, octane etc., halogenated aliphatic or aromatic hydrocarbons, for example dichloromethane, 1,2-dichloroethane, carbon tetrachloride, 1,1,2,2-tetrachloroethane, trichloromethane and trichloroethane, chlorobenzene, dichlorobenzenes, trichlorobenzene etc., ethers, for example diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc., nitriles, for example acetonitrile, propionitrile, etc., amides, for example dimethylformamide, methylpyrrolidone, diethylformamide, etc., sulfoxides, for example dimethyl sulfoxide etc.
Preference is given to halogenated, aliphatic or aromatic solvents from the group dichloromethane, 1,2-dichloroethane, carbon tetrachloride, 1,1,2,2-tetrachloroethane, trichloromethane and trichloroethane, chlorobenzene and dichlorobenzenes.
The reaction temperature is from xe2x88x9240xc2x0 C. to +30xc2x0 C., preferably from xe2x88x9230xc2x0 C. to +10xc2x0 C. and especially from xe2x88x9220xc2x0 C. to 0xc2x0 C.
The reaction mixture is stirred at the appropriate reaction temperature for from a few minutes up to several hours. Stirring is preferably carried out for from about 5 minutes up to 5 hours and especially for from about 20 minutes up to 2 hours.
The reaction of allyl isothiocyanate and chlorinating agent yields an intermediate compound of formula 
which is not, however, isolated from the reaction mixture.
The reaction mixture obtained by step a), which contains the above intermediate compound, is immediately after step a) subjected to the following reaction with oxidising agent (step b). For that purpose, in step b) either from 1 to 5 mol of oxidising agent per mol of allyl isothiocyanate are added to the reaction mixture. Suitable oxidising agents are, for example, peroxy acid, for example peracetic acid, m-chloroperbenzoic acid, acid/H2O2 mixtures, inorganic or organic peroxides, for example nickel peroxide, hydroperoxides or quinones, for example dichlorodicyanoquinone.
It is also possible, however, for from 1 to 5 mol of an oxidising agent that acts simultaneously as halogenating agent to be added to the reaction mixture, the oxidation being carried out by halogenation and subsequent dehydrohalogenation. Preferred halogenating agents are chlorinating or brominating compounds, such as Cl2, Br2, sulfuryl chloride, N-haloimides, for example N-chloro- or N-bromo-succinimide or N-chloro- or N-bromo-phthalimide, or dihalodialkylhydantoins, for example dichlorodimethylhydantoin.
It is preferable to use from 1.2 to 4 mol and especially from 1.8 to 3 mol of oxidising agent or halogenating agent per mol of allyl isothiocyanate.
The oxidising agent or halogenating agent used is preferably a chlorinating or brominating compound and especially N-chloro- or N-bromo-succinimide, N-chloro- or N-bromo-phthalimide and dichlorodimethylhydantoin.
When a halogenating compound is used as oxidising agent, substitution takes place which, for example, is initiated or accelerated by UV light and/or by addition of a suitable initiator. Suitable initiators are customary compounds known from the prior art. They are, for example, peroxides, for example dibenzoyl peroxide, diacetyl peroxide, azo compounds, for example azobisisobutyronitrile, etc.
The initiator is used in an amount of from 0.05 to 10 mol %, preferably from 0.1 to 8 mol % and especially from 0.5 to 5 mol %, based on allyl isothiocyanate.
The oxidising agent and/or the initiator can be added either in one portion or divided into several portions.
The reaction temperature is from 0xc2x0 C. to the boiling point of the solvent used. The reaction temperature is preferably from 20xc2x0 C. to the boiling point of the solvent used and especially about from 30 to 80xc2x0 C.
It is especially advantageous to the purity of the CCT when the reactions according to steps a) and b) are carried out under conditions that are as water-free as possible. This is achieved by the use of absolute solvents and pure allyl isothiocyanate, and if necessary by working under an inert gas atmosphere.
For the isolation and working-up of the CCT prepared, the reaction mixture is optionally first cooled.
When a N-haloimide is used as oxidising agent, precipitated imide is separated off, for example, optionally by filtration. The reaction mixture that remains behind is then rendered basic in order to bind any acids present, such as HCI or HBr. This can be carried out, for example, by washing with, or by adding, suitable bases. Suitable bases are, for example, NaHCO3 solutions, KHCO3 solutions, Na2CO3 solutions, K2CO3 solutions, dilute NaOH or KOH, aqueous ammonia, dry Na2CO3 or K2CO3 etc.
The solvent is then separated off and the crude CCT is purified, for example by simple distillation.
For further increasing the purity, the CCT-containing distillate can then be subjected to crystallisation and washing with, or digestion in, an aliphatic hydrocarbon, such as hexane, heptane etc., in an ether or ester. Aliphatic hydrocarbons are preferred.
Accordingly, in order to obtain high-purity CCT, the distillate (if necessary after separation of precipitated imide, basic washing, separation of the solvent and distillation) is preferably crystallised out by cooling to from 0 to xe2x88x9240xc2x0 C., preferably to from xe2x88x925 to xe2x88x9240xc2x0 C. and especially to from xe2x88x9215 to xe2x88x9240xc2x0 C., the crystals are filtered off with suction and digested while cold in an aliphatic, preferably ice-cold hydrocarbon, preferably in hexane or heptane, or in an ether or ester and then dried at room temperature in vacuo, if necessary under a nitrogen atmosphere.
During the crystallisation, the liquid above the crystals contains generally up to 29% by weight CCT, that is to say with CCT concentrations of 30% and more it is possible to obtain high-purity material from crude products of that kind.
By crystallisation it is possible, however, to increase the purity not only of distillates but also of solid commercially available CCT. For that purpose, the CCT to be purified is first dissolved in an aliphatic hydrocarbon, an ether or ester; active carbon is optionally added to the solution and any solids present are filtered off. Crystallisation and subsequent digestion are then carried out analogously to the above description.
The reaction procedure according to the invention yields CCT in substantially higher purities than in the prior art. As comparison experiments show, crude CCT prepared in accordance with the invention has scarcely any high molecular weight secondary products, as are the case, for example, with CCT prepared in accordance with EP 0 260 560.
Those high molecular weight secondary products cannot be identified or can be identified only with extreme difficulty by means of GC, but can be detected by means of HPLC-MS. By the working-up and purification according to the invention, CCT is obtained in substantially higher purities than in the prior art.
A further advantage of the process according to the invention is that it is performed in the form of a one-pot reaction which does not require complex apparatus.